The role of immunologic mechanisms in autoimmune disorders and virus has been the focus of increasing interest and investigation. Among the autoimmune disorders that have been studied are multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, polymyositis, myasthenia gravis, Sjogren's disease and hemolytic anemias.
Certain autoimmune diseases affect primarily the nervous system. Autoimmune diseases of this type include the demyelinating diseases such as multiple sclerosis, (central nervous system) and acute idiopathic polyneuritis (Guillian-Barre' Syndrome) (peripheral nervous system).
Multiple sclerosis is a chronic relapsing disease which affects many areas of the central nervous system white matter. A major feature of multiple sclerosis is inflammatory demyelination in the central nervous system with lesions primarily in the periventricular areas of the cerebrum, cerebellum, brain stem and spinal cord. Common manifestations of multiple sclerosis are motor weakness, paresthesias, impairment of visual acuity and diplopia.
To better understand human demyelinating diseases, such as multiple sclerosis, viral diseases of the central nervous system of mice, such as Theiler's murine encephalomyelitis virus (TMEV), have been studied. TMEV is a picornavirus, which induces an unusual biphasic neurologic disease of the central nervous system in susceptible mice (M. Theiler, Science, 80: 122 (1934); H. L. Lipton, Infect. Immuno., 11: 1147 (1975)). The disease produced by Theiler's "original" (TO) strain of virus [H. L. Lipton and M. C. Dal Canto, Ann. Neurol., 6: 25 (1979)] is characterized by acute neuronal polioencephalitis followed by chronic primary demyelination with persistence of virus in glial cells (M. Rodriguez et al., Ann. Neurol., 13: 426 (1983)). Infection with tissue culture-adapted strains of TMEV results in prominent myelin destruction but minimal polioencephalitis, even though neurons produce vital antigens during the acute phase.
It has been suggested that the chronic demyelination induced by TMEV is mediated by immune cells. The pathologic features are strikingly similar to those of experimental autoimmune encephalomyelitis (EAE) with lymphocytes present in a perivascular distribution in the brain and spinal cord (M. C. Dal Canto and H. L. Lipton, Lab. Invest., 33: 626 (1975)). Furthermore, immunosuppression with cyclophosphamide [H. L. Lipton and M. C. Dal Canto, Science, 192: 62 (1976); H. L. Lipton and M. C. Dal Canto, Infect. Immun., 15: 903 (1977)], antitymphocyte serum [R. P. Roos et al., J. Neuroimmunol., 2: 223 (1982)], cyclosporin A [M. Rodriguez and J. Quddus, J. Neuroimmunol., 13: 159 (1986)], or monoclonal antibody to immune-response gene products [M. Rodriguez et al., Neurology, 36: 964 (1986); Friedmann et al., J. Virol., 61: 898 (1987)] partially suppresses demyelination.
Demyelination may result as an immune response directed against persistently infected oligodendrocytes (myelin-producing cells) (Rodriguez et al., Immunol. Today, 7: 359 (1986)). As a consequence of viral infection, antigens not associated with normal oligodendrocytes would appear on the cell surface and be recognized by T cells in association with MHC glycoproteins. Accordingly, there is a need to provide a method for blocking cytolytic activity of T cells which recognize cell surface antigens not associated with normal (non-virus) infected cells; thereby, providing a method to suppress inflammation and demyelination in patients suffering from autoimmune diseases affecting the central nervous system.